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Introduction: Executive function deficits and adverse psychological outcomes are common in youth with congenital heart disease (CHD) or born preterm. Association white matter bundles play a critical role in higher order cognitive and emotional functions and alterations to their microstructural organization may result in adverse neuropsychological functioning. This study aimed to examine the relationship of myelination and axon density and orientation alterations within association bundles with executive functioning, psychosocial well-being, and resilience in youth with CHD or born preterm., Methods: Youth aged 16 to 26 years born with complex CHD or preterm at ≤33 weeks of gestational age and healthy controls completed a brain MRI and self-report assessments of executive functioning, psychosocial well-being, and resilience. Multicomponent driven equilibrium single-pulse observation of T 1 and T 2 and neurite orientation dispersion and density imaging were used to calculate average myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index values for eight bilateral association bundles. The relationships of bundle-average metrics with neuropsychological outcomes were explored with linear regression and mediation analyses., Results: In the CHD group, lower MWF in several bundles was associated with poorer working memory and behavioral self-monitoring and mediated self-monitoring deficits relative to controls. In the preterm group, lower NDI in several bundles was associated with poorer emotional control and lower MWF in the left superior longitudinal fasciculus III mediated planning/organizing deficits relative to controls. No significant relationships were observed for psychosocial well-being or resilience., Conclusion: The findings of this study suggest that microstructural alterations to association bundles, including lower myelination and axon density, have different relationships with executive functioning in youth with CHD and youth born preterm. Future studies should aim to characterize other neurobiological, social, and environmental influences that may interact with white matter microstructure and neuropsychological functioning in these at-risk individuals., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objective: To characterize the psychological well-being, everyday functioning, and autonomy of emerging adults with congenital heart disease (CHD) and explore how they relate to the executive function (EF) deficits commonly observed in this population., Study Design: Questionnaires assessing psychological well-being (encompassing psychosocial functioning and resilience), EF, and age-appropriate indicators of everyday function and autonomy (eg, housing, education, employment, relationship status) were completed by participants with CHD (16-26 years) who underwent open-heart surgery during infancy and age- and sex-matched controls., Results: A total of 58 emerging adults with CHD and 57 controls participated in this study. Mean scores on the resilience and psychosocial functioning questionnaires were not significantly different between CHD and control participants. Emerging adults with CHD also did not differ from controls in terms of holding a driver's license, involvement in a romantic relationship, or current employment status. Multiple linear regression identified that better EF was associated with better psychological well-being., Conclusions: This study supports the need for systematic screening for EF deficits during adolescence and early adulthood to promote optimal well-being in this population. Further research is required to continue to document the everyday experiences of adolescents and young adults with CHD to identify protective factors associated with a successful and satisfying transition to adult life., Competing Interests: Declaration of Competing Interest The authors of this paper do not have any conflict of interest to disclose. This work was funded by the Research Institute of the McGill University Health Centre and the Faculty of Medicine of McGill University. F.A. received studentship support from Canada Graduate Scholarships (Canadian Institutes of Health Research). K.E. received studentship support from the Vanier Canada Graduate Scholarship (Canadian Institutes of Health Research). M.B.R. is supported by a Canada Research Chair in Brain and Child Development (Canadian Institutes of Health Research)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Lower cerebral blood flow (CBF) has previously been documented preoperatively in neonates with congenital heart disease (CHD). However, it remains unclear if these CBF deficits persist over the life span of CHD survivors following heart surgery. When exploring this question, it is critical to consider the sex differences in CBF that emerge during adolescence. Therefore, this study aimed to compare global and regional CBF between postpubertal youth with CHD and healthy peers and examine if such alterations are related to sex. Methods and Results Youth aged 16 to 24 years who underwent open heart surgery for complex CHD during infancy and age- and sex-matched controls completed brain magnetic resonance imaging, including T1-weighted and pseudo-continuous arterial spin labeling acquisitions. Global gray matter CBF and regional CBF in 9 bilateral gray matter regions were quantified for each participant. Compared with female controls (N=27), female participants with CHD (N=25) presented with lower global and regional CBF. In contrast, there were no differences in CBF between male controls (N=18) and males with CHD (N=17). Concurrently, female controls had higher global and regional CBF compared with male controls, with no differences in CBF between female and male participants with CHD. CBF was lower in individuals with a Fontan circulation. Conclusions This study provides evidence of altered CBF in postpubertal female participants with CHD despite undergoing surgical intervention during infancy. Alterations to CBF could have implications for later cognitive decline, neurodegeneration, and cerebrovascular disease in women with CHD.

Introduction: Alterations to white matter microstructure as detected by diffusion tensor imaging have been documented in both individuals born with congenital heart disease (CHD) and individuals born preterm. However, it remains unclear if these disturbances are the consequence of similar underlying microstructural disruptions. This study used multicomponent driven equilibrium single pulse observation of T 1 and T 2 (mcDESPOT) and neurite orientation dispersion and density imaging (NODDI) to characterize and compare alterations to three specific microstructural elements of white matter - myelination, axon density, and axon orientation - in youth born with CHD or born preterm., Methods: Participants aged 16 to 26 years with operated CHD or born ≤33 weeks gestational age and a group of healthy peers of the same age underwent a brain MRI including mcDESPOT and high angular resolution diffusion imaging acquisitions. Using tractometry, average values of myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index (ODI) were first calculated and compared between groups for 30 white matter bundles. Afterwards, bundle profiling was performed to further characterize the topology of the detected microstructural alterations., Results: The CHD and preterm groups both presented with widespread bundles and bundle segments with lower MWF, accompanied by some occurrences of lower NDI, relative to controls. While there were no differences in ODI between the CHD and control groups, the preterm group presented with both higher and lower ODI compared to the control group and lower ODI compared to the CHD group., Discussion: While youth born with CHD or born preterm both presented with apparent deficits in white matter myelination and axon density, youth born preterm presented with a unique profile of altered axonal organization. Future longitudinal studies should aim to better understand the emergence of these common and distinct microstructural alterations, which could orient the development of novel therapeutic approaches., Competing Interests: GG is an employee of Philips Healthcare Canada. MD is an employee, co-founder, and co-owner of Imeka Solutions Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Easson, Khairy, Rohlicek, Saint-Martin, Gilbert, Nguyen, Luu, Couture, Nuyt, Wintermark, Deoni, Descoteaux and Brossard-Racine.)

Brain injury and dysmaturation is common in fetuses and neonates with congenital heart disease (CHD) and is hypothesized to result in persistent myelination deficits. This study aimed to quantify and compare myelin content in vivo between youth born with CHD and healthy controls. Youth aged 16 to 24 years born with CHD and healthy age- and sex-matched controls underwent brain magnetic resonance imaging including multicomponent driven equilibrium single pulse observation of T 1 and T 2 (mcDESPOT). Average myelin water fraction (MWF) values for 33 white matter tracts, as well as a summary measure of average white matter MWF, the White Matter Myelination Index, were calculated and compared between groups. Tract-average MWF was lower throughout the corpus callosum and in many bilateral association tracts and left hemispheric projection tracts in youth with CHD (N = 44) as compared to controls (N = 45). The White Matter Myelination Index was also lower in the CHD group. As such, this study provides specific evidence of widespread myelination deficits in youth with CHD, likely representing a long-lasting consequence of early-life brain dysmaturation in this population. This deficient myelination may underlie the frequent neurodevelopmental impairments experienced by CHD survivors and could eventually serve as a biomarker of neuropsychological function., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Congenital heart disease is a leading cause of neurocognitive impairment. Many subcortical structures are known to play a crucial role in higher-order cognitive processing. However, comprehensive anatomic characterization of these structures is currently lacking in the congenital heart disease population. Therefore, this study aimed to compare the morphometry and volume of the globus pallidus, striatum, and thalamus between youth born with congenital heart disease and healthy peers., Materials and Methods: We recruited youth between 16 and 24 years of age born with congenital heart disease who underwent cardiopulmonary bypass surgery before 2 years of age ( n = 48) and healthy controls of the same age ( n = 48). All participants underwent a brain MR imaging to acquire high-resolution 3D T1-weighted images., Results: Smaller surface area and inward bilateral displacement across the lateral surfaces of the globus pallidus were concentrated anteriorly in the congenital heart disease group compared with controls ( q  < 0.15). On the lateral surfaces of bilateral thalami, we found regions of both larger and smaller surface areas, as well as inward and outward displacement in the congenital heart disease group compared with controls ( q  < 0.15). We did not find any morphometric differences between groups for the striatum. For the volumetric analyses, only the right globus pallidus showed a significant volume reduction ( q  < 0.05) in the congenital heart disease group compared with controls., Conclusions: This study reports morphometric alterations in youth with congenital heart disease in the absence of volume reductions, suggesting that volume alone is not sufficient to detect and explain subtle neuroanatomic differences in this clinical population., (© 2020 by American Journal of Neuroradiology.)

Background: White matter alterations have previously been demonstrated in adolescents born with congenital heart disease (CHD) using diffusion tensor imaging (DTI). However, due to the non-specific nature of DTI metrics, it is difficult to interpret these findings in terms of their microstructural implications. This study investigated the use of neurite orientation dispersion and density imaging (NODDI), which involves the acquisition of advanced multiple b-value data over two shells and provides proxy measures of apparent axon density and orientation dispersion within white matter, as a complement to classic DTI measures., Study Design: Youth aged 16 to 24 years born with complex CHD and healthy peers underwent brain magnetic resonance imaging. White matter tract volumes and tract-average values of DTI and NODDI metrics were compared between groups. Tract-average DTI and NODDI results were spatially confirmed using tract-based spatial statistics., Results: There were widespread regions of lower tract-average neurite density index (NDI) in the CHD group as compared to the control group, particularly within long association tracts and in regions of the corpus callosum, accompanied by smaller white matter tract volumes and isolated clusters of lower fractional anisotropy (FA). There were no significant differences in orientation dispersion index (ODI) between groups., Conclusion: Lower apparent density of axonal packing, but not altered axonal orientation, is a key microstructural factor in the white matter abnormalities observed in youth born with CHD. These impairments in axonal packing may be an enduring consequence of early life brain injury and dysmaturation and may explain some of the long-term neuropsychological difficulties experienced by this at-risk group., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There is a high prevalence of neurodevelopmental impairments in individuals living with congenital heart disease (CHD) and the neural correlates of these impairments are not yet fully understood. Recent studies have shown that hippocampal volume and shape differences may provide unique biomarkers for neurodevelopmental disorders. The hippocampus is vulnerable to early life injury, especially in populations at risk for hypoxemia or hemodynamic instability such as in neonates with CHD. We compared hippocampal gray and white matter volume and morphometry between youth born with CHD (n = 50) aged 16-24 years and healthy peers (n = 48). We also explored whether hippocampal gray and white matter volume and morphometry are associated with executive function and self-regulation deficits. To do so, participants underwent 3T brain magnetic resonance imaging and completed the self-reported Behavior Rating Inventory of Executive Function-Adult version. We found that youth with CHD had smaller hippocampal volumes (all statistics corrected for false discovery rate; q < 0.05) as compared to controls. We also observed significant smaller surface area bilaterally and inward displacement on the left hippocampus predominantly on the ventral side (q < 0.10) in the CHD group that were not present in the controls. Left CA1 and CA2/3 were negatively associated with working memory (p < .05). Here, we report, for the first-time, hippocampal morphometric alterations in youth born with CHD when compared to healthy peers, as well as, structure-function relationships between hippocampal volumes and executive function. These differences may reflect long lasting alterations in brain development specific to individual with CHD., (© 2019 Wiley Periodicals, Inc.)

Background: Congenital atrioventricular block is a well-established immunologic complication of maternal systemic lupus erythematosus. We sought to further characterize the electrophysiological manifestations of maternal systemic lupus erythematosus on neonatal atria., Methods and Results: Cases of isolated congenital atrioventricular block treated at our center over the past 41 years were identified. Data were extracted from clinical charts, pacemaker interrogations, ECGs, echocardiograms, and histopathological reports, when available. Of 31 patients with isolated congenital atrioventricular block, 18 were negative for maternal antibodies and had normal epicardial atrial sensing and pacing thresholds. In contrast, 12 of 13 patients with positive maternal antibodies had epicardial pacemakers, 5 (42%) of whom had left atrial (LA) inexcitability and/or atrial conduction delay. In 3 patients, the LA could not be captured despite high-output pacing. The fourth patient had acutely successful LA appendage and left ventricular lead placement. At early follow-up, an increased delay between the surface P-wave and intracardiac atrial depolarization was observed, indicative of atrial conduction delay. The fifth patient exhibited LA lead dysfunction, with atrial under-sensing and an increased capture threshold, 2 weeks after implantation. Biopsies of LA appendages performed in 2 patients showed no evidence of atrial fibrosis or loss of atrial myocytes., Conclusions: Herein, we report previously undescribed yet prevalent electrophysiological ramifications of maternal systemic lupus erythematosus, which extend beyond congenital atrioventricular block to encompass alterations in LA conduction, including LA inexcitability. These manifestations can complicate epicardial pacemaker implantation in newborns. In the absence of histological evidence of extensive atrial fibrosis, immune-mediated functional impairment of electrical activity is suspected., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: To determine the effect of experimentally induced hypoxia, in the first 10 days of life, on physiological hearing in a Sprague-Dawley rat model. Methods: A prospective, controlled animal study was carried out using 22 male rat pups. The rats in the hypoxic group (n = 12) were reared in hypoxia for the first 10 days of life, and subsequently reared in normoxia, while those in the control group (n = 10) were reared in normoxia for the duration of the experiment. Hearing was assessed using auditory brainstem response testing at approximately 72 days of age. Results: The hypoxia group had higher auditory brainstem response thresholds for all frequencies tested (more pronounced at 16 kHz), compared with controls. Wave I-V inter-peak latencies were more prolonged in the hypoxic rats, while both groups had similar wave I latencies. Conclusion: Chronic postnatal hypoxia induced permanent hearing loss in this Sprague-Dawley rat model. Prolonged wave I-V inter-peak latencies suggested functional abnormality in the central auditory pathway.

Data suggest that despite improved surgical outcomes for infants with hypoplastic left heart syndrome (HLHS), the past two decades have seen little change in parents' decisions whether to choose surgery or palliative treatment without life-prolonging intervention. Data also suggest that doctors' predictions of the choices they would make if their own infant were diagnosed with HLHS do not correlate with their predictions of surgical outcomes. Although previous studies have compared rates of surgery and palliative treatment without life-prolonging intervention over time, no studies have assessed changes in doctors' attitudes. The current study used descriptive and quantitative statistics to compare responses from American pediatric cardiologists and congenital cardiac surgeons from studies conducted in 1999 and 2007. These doctors were asked what choice they believe they would make for their own affected infant. Comparison of responses from 1999 and 2007 showed no difference in the responses of cardiologists: 1999 (44 % surgery, 17 % palliative treatment, 40 % uncertain) versus 2007 (45 % surgery, 20 % palliative treatment, 35 % uncertain). Among surgeons, there was a non-statistically significant trend away from choosing surgery: 1999 (77 % surgery, 5 % palliative treatment, 18 % uncertain) versus 2007 (56 % surgery, 8 % palliative treatment, 36 % uncertain). In conclusion, these analyses suggest that despite improving surgical outcomes, doctors are no more likely to predict that they would choose surgery for their own hypothetical infant with HLHS. Further research is needed to determine what factors influence choice making in the care of infants with HLHS.

Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C.T, MTHFR c.1298A.C, methionine synthase reductase (MTRR) c.66A.G, and reduced folate carrier (SLC19A1) c.80A.G) in a case-control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A.G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18-0.97) and 0.39 (0.18-0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11-0.91) and 0.25 (0.09-0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09-0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22-6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C.T or SLC19A1 c.80A.G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk.

Di-(2-ethylhexyl) phthalate (DEHP) is used industrially to add flexibility to polyvinyl chloride (PVC) polymers and is ubiquitously found in the environment, with evidence of prenatal, perinatal and early infant exposure in humans. In utero exposure to DEHP decreases circulating testosterone levels in the adult rat. In addition, DEHP reduces the expression of the angiotensin II receptors in the adrenal gland, resulting in decreased circulating aldosterone levels. The latter may have important effects on water and electrolyte balance as well as systemic arterial blood pressure. Therefore, we determined the effects of in utero exposure to DEHP on systemic arterial blood pressure in the young (2month-old) and older (6.5month-old) adult rats. Sprague-Dawley pregnant dams were exposed from gestational day 14 until birth to 300mg DEHP/kg/day. Blood pressure, heart rate, and activity data were collected using an intra-aortal transmitter in the male offspring at postnatal day (PND) 60 and PND200. A low (0.01%) and high-salt (8%) diet was used to challenge the animals at PND200. In utero exposure to DEHP resulted in reduced activity at PND60. At PND200, systolic and diastolic systemic arterial pressures as well as activity were reduced in response to DEHP exposure. This is the first evidence showing that in utero exposure to DEHP has cardiovascular and behavioral effects in the adult male offspring., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: There is a growing population of adults with repaired cyanotic congenital heart disease. These patients have increased risk of impaired cardiac health and premature death. We hypothesized that hypoxia in early life before surgical intervention causes lasting changes in left ventricular structure and function with physiological implications in later life., Methods: Sprague-Dawley rats reared initially hypoxic conditions (FiO(2)=0.12) for days 1-10 of life were compared to rats reared only in ambient air. Cellular morphology and viability were compared among LV cardiomyocytes and histological analyses were performed on LV myocardium and arterioles. Intracellular calcium transients and cell shortening were measured in freshly-isolated cardiomyocytes, and mitochondrial hexokinase 2 (HK2) expression and activity were determined. Transthoracic echocardiography was used to assess LV function in anesthetized animals., Results: Cardiomyocytes from adult animals following hypoxia in early life had greater cellular volumes but significantly reduced viability. Echocardiographic analyses revealed LV hypertrophy and diastolic dysfunction, and alterations in cardiomyocyte calcium transients and cell shortening suggested impaired diastolic calcium reuptake. Histological analyses revealed significantly greater intima-media thickness and decreased lumen area in LV arterioles from hypoxic animals. Alterations in mitochondrial HK2 protein distribution and activity were also observed which may contribute to cardiomyocyte fragility., Conclusions: Hypoxia in early life causes lasting changes in left ventricular structure and function that may negatively influence myocardial and vascular responses to physiological stress in later life. These data have implications for the growing population of adults with repaired or palliated cyanotic congenital heart disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The management of pediatric discrete subaortic stenosis remains controversial., Objectives: Document the natural history and surgical outcomes for discrete subaortic stenosis to adolescence., Methods: Retrospective review of clinical and echocardiographic findings in 74 patients diagnosed in childhood between 1985 and 1998., Results: Twenty-five patients were followed only medically for 9.4 ± 0.9 years to 15.9 ± 0.6 years of age. Their echocardiographic left ventricular outflow peak gradient did not progress, 19 ± 1.4 (SEM) vs 20 ± 2.3 mm Hg. The proportion with aortic insufficiency (AI) increased (4% to 52%). Forty-nine patients were operated for discrete subaortic stenosis at 7.8 ± 0.6 years. Their peak gradient at diagnosis was 36 ± 3 mm Hg with AI in 33%. Preoperatively their peak gradient progressed to 60 ± 5 mm Hg with AI in 82%. Assessment 6.2 ± 0.5 years postoperativly showed a peak gradient of 14 ± 2 mm Hg with AI in 88%. Ten patients required reoperation for recurrent discrete subaortic stenosis, 3 acquired complete heart block, and 1 developed endocarditis. There was no mortality. At diagnosis, surgical patients were younger, had greater peak gradients, and greater incidence of AI, than those followed only medically. The progression of discrete subaortic stenosis was positively associated with severity of obstruction and negatively associated with older age at diagnosis. The risk of having surgery over time was associated with greater preoperative obstruction and presence of AI., Conclusions: Many pediatric patients with mild discrete subaortic stenosis exhibit little progression of obstruction and need not undergo immediate surgery. Others with more severe stenosis may progress precipitously and will benefit from early resection., (Copyright © 2011. Published by Elsevier Inc.)

Both β(1)- and β(3)-adrenergic receptors (β(1)ARs and β(3)ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the βAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially reversed this effect. Our results suggest that GPCRs on the nuclear membrane regulate nuclear functions such as gene expression and this process is modulated by activation/inhibition of downstream protein kinases within the nucleus., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The effect of prolonged hypoxemia in early life on systemic arterial blood pressure at maturity was assessed in Sprague-Dawley rats., Methods: Animals hypoxic in early life (12 males, 10 females) were raised in hypoxia (FiO₂ = 0.12) for the first 10 days of life and subsequently raised in normoxia, along with age-matched controls (11 males, 9 females). At 2 months of age, arterial blood pressure was recorded intravascularly using telemetry in awake and unrestrained animals over two 12-h night-time (active) and daytime (resting) periods. Aortic pulse wave velocity was assessed in six additional hypoxic pretreated and five control anesthetized 2-month-old male rats., Results: Systolic, mean, and pulse pressures were significantly greater in the hypoxic pretreated group compared to the control group during resting and active periods in both sexes (P ≤ 0.05). Diastolic pressure and heart rate did not differ between the two groups. Hypoxic pretreated males displayed significantly increased blood pressure variability during the resting period. Aortic pulse wave velocity was also found to be elevated in the hypoxic pretreated rats., Conclusions: Prolonged hypoxic stress in early life in the rat is associated with increased systolic arterial pressure at maturity very likely due to decreased arterial compliance. These findings suggest that a nutrient-independent, postnatal stress may lead to long-lasting vascular alterations predisposing to increased arterial pressure at maturity. This raises the possibility that adult survivors of congenital cyanotic cardiac disease may be at risk for secondary cardiovascular morbidity unrelated to surgical repair or residual cardiac defects.

Objective: We conducted a survey to determine which management options pediatric cardiologists and cardiac surgeons in North America discuss and recommend when counseling parents after the diagnosis of hypoplastic left heart syndrome (HLHS)., Methods: Pediatric cardiologists and cardiac surgeons across North America were asked to complete an anonymous, Internet-based survey about their attitudes and practices regarding the management of HLHS., Results: We contacted 1621 pediatric cardiologists and surgeons, of whom 749 (46%) completed the survey. When counseling parents of newborns with HLHS, 99.7% of respondents discussed staged palliative surgery, 67% discussed cardiac transplantation, and 62.2% discussed compassionate care without surgery. Only a minority (14.9%) discussed all of those options. Staged palliative surgery was recommended over cardiac transplantation or compassionate care without surgery by 76.2% of respondents. When counseling parents after prenatal diagnosis of HLHS, 98.8% of respondents discussed continuation of pregnancy with staged palliative surgery after birth, 53.5% discussed continuation of pregnancy with cardiac transplantation after birth, 56.9% discussed continuation of pregnancy with compassionate care after birth, and 74.3% discussed termination of pregnancy. Only 36.5% discussed all of those options. Continuation of pregnancy with staged palliative surgery after birth was recommended over the other options by 56% of respondents., Conclusions: Virtually all North American pediatric cardiologists and cardiac surgeons surveyed discuss a surgical intervention when counseling parents about the care of their child or fetus with HLHS. However, only a minority discuss all options. Most physicians recommend staged palliative surgery for management of HLHS.

Nestin+ cardiac myocyte-like cells were detected in the peri-infarct/infarct region of the ischemically damaged heart. The present study was undertaken to elucidate the phenotype and potential origin of nestin+ cardiac myocyte-like cells and identify stimuli implicated in their appearance. In the infarcted human and rat heart, nestin+ cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the beta(1)-adrenergic receptor, and associated with an aberrant pattern of connexin-43 expression and/or organization. Nestin+ cardiac myocyte-like cells were detected 24 h postischemic injury and persisted in the infarcted rat heart for 9 mo. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin+ neural stem cells. Following an ischemic insult, nestin+/Nkx2.5+ neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin+ cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for 10 days failed to promote the appearance of nestin+ cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin+ cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss. Thus ischemia-induced appearance of nestin+ cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin+ cardiac myocyte-like cell.

Objective: Innovations in pediatric cardiovascular surgery have resulted in significant improvements in survival for children with congenital heart disease. In adults with such disease, however, surgical morbidity and mortality remain significant. We hypothesized that hypoxemia in early life causes lasting changes in gene expression in the developing heart and that such changes may persist into later life, affecting the physiology of the adult myocardium., Methods: Microarray expression analyses were performed with left ventricular tissue from 10- and 90-day-old rats exposed to hypoxia (inspired oxygen fraction 0.12) for the first 10 days after birth then subsequently reared in ambient air and with tissue from age-matched rats reared entirely in ambient air. Changes in expression of selected genes were confirmed with real-time reverse transcriptase polymerase chain reaction. Left ventricular cardiomyocytes were isolated from adult animals in both groups, and cellular morphology and viability were compared., Results: Microarray analyses revealed significant changes in 1945 and 422 genes in neonates and adults, respectively. Changes in genes associated with adaptive vascular remodeling and energy homeostasis, as well as regulation of apoptosis, were confirmed by real-time reverse transcriptase polymerase chain reaction. The viability of cardiomyocytes isolated from hypoxic animals was significantly lower than in those from control animals (36.7% +/- 13.3% vs 85.0% +/- 2.9%, P = .024)., Conclusions: Neonatal hypoxia is associated with significant changes in left ventricular gene expression in both neonatal and adult rats. This may have physiologic implications for the adult myocardium.

Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis. A common variant in MTHFD1, p.Arg653Gln (c.1958G>A), may increase the risk for neural tube defects (NTD). To examine the biological impact of this variant on MTHFD1 function, we measured enzyme activity and stability in vitro and assessed substrate flux in transfected mammalian cells. The purified Arg653Gln enzyme has normal substrate affinity but a 36% reduction in half)life at 42 degrees C. Thermolability is reduced by magnesium adenosine triphosphate and eliminated by the substrate analog folate pentaglutamate, suggesting that folate status may modulate impact of the variant. The mutation reduces the metabolic activity of MTHFD1 within cells: formate incorporation into DNA in murine Mthfd1 knockout cells transfected with Arg653Gln is reduced by 26%+/-7.7% (P<0.05), compared to cells transfected with wild)type protein, indicating a disruption of de novo purine synthesis. We assessed the impact of the variant on risk for congenital heart defects (CHD) in a cohort of Quebec children (158 cases, 110 controls) and mothers of children with heart defects (199 cases, 105 controls). The 653QQ genotype in children is associated with increased risk for heart defects (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.01-4.42), particularly Tetralogy of Fallot (OR, 3.60; 95% CI, 1.38-9.42) and aortic stenosis (OR, 3.13; 95% CI, 1.13-8.66). There was no effect of maternal genotype. Our results indicate that the Arg653Gln polymorphism decreases enzyme stability and increases risk for CHD. Further evaluation of this polymorphism in folate)related disorders and its potential interaction with folate status is warranted., ((c) 2008 Wiley-Liss, Inc.)

Objectives: To determine the sensitivity and specificity of the clinical assessment of murmurs in neonates, as performed by pediatric cardiologists, and to identify clinical features that predict the presence of congenital heart disease (CHD) in this population., Study Design: Neonates (n = 201) referred for outpatient evaluation of a heart murmur were enrolled consecutively. After a clinical evaluation, the cardiologist documented whether the murmur was "likely innocent" or "likely pathologic." The cardiologist repeated his/her assessment after an electrocardiogram. Echocardiography served as the gold standard., Results: The median age was 12 days (range, 2-31 days). CHD was present in 113 of 201 (56%). Clinical assessment alone identified patients with CHD with a sensitivity of 80.5% (95% CI, 73.2-87.8), specificity of 90.9% (95% CI, 84.9-96.9), positive predictive value of 91.9% (95% CI, 86.6-97.3), and negative predictive value of 78.4% (95% CI, 70.4-86.4). The addition of an electrocardiogram did not improve these test characteristics. Features that were predictive of CHD were murmur quality (P < .0001), location (P = .02), and timing (P = .04). No patients requiring catheter or surgical intervention were missed by clinical assessment., Conclusions: The prevalence of CHD in this referral population was high. Clinical assessment detected all complex CHD, although some simple lesions were missed. Murmur quality, location, and timing were predictive of CHD.

Decreased right as well as left ventricular function can be associated with pulmonary hypertension (PH). Numerous investigations have examined cardiac function following induction of pulmonary hypertension with monocrotaline (MCT) assuming that MCT has no direct cardiac effect. We tested this assumption by examining left ventricular function and histology of isolated and perfused hearts from MCT-treated rats. Experiments were performed on 50 male Sprague-Dawley rats [348 +/- 6 g (SD)]. Thirty-seven rats received MCT (50 mg/kg sc; MCT group) while the remainder did not (Control group). Three weeks later, pulmonary artery pressure was assessed echocardiographically in 20 MCT and 8 Control rats. The hearts were then excised and perfused in the constant pressure Langendorff mode to determine peak left ventricular pressure (LVP), the peak instantaneous rate of pressure increase (+dP/dtmax) and decrease (-dP/dtmax), as well as the rate pressure product (RPP). Histological sections were subsequently examined. Pulmonary artery pressure was higher in the MCT-treated group compared with the Control group [12.9 +/- 6 vs. 51 +/- 35.3 mmHg (P < 0.01)]. Left ventricular systolic function and diastolic relaxation were decreased in the MCT group compared with the Control group (+dP/dtmax 4,178 +/- 388 vs. 2,801 +/- 503 mmHg/s, LVP 115 +/- 11 vs. 83 +/- 14 mmHg, RPP 33,688 +/- 1,910 vs. 23,541 +/- 3,858 beats x min(-1) x mmHg(-1), -dP/dtmax -3,036 +/- 247 vs. -2,091 +/- 389 mmHg/s; P < 0.0001). The impairment of cardiac function was associated with myocarditis and coronary arteriolar medial thickening. Similarly depressed ventricular function and inflammatory infiltration was seen in 12 rats 7 days after MCT administration. Our findings appear unrelated to the degree of PH and indicate a direct cardiotoxic effect of MCT.

Background: Previous experiments have shown that warming hypoxic infants reduces total peripheral vascular resistance. This suggests that the usual vasoconstriction of less essential vascular beds during hypoxia may be reduced and that the normal redistribution of blood flow to more vital organs may be compromised., Objective: Evaluate the effect of body warming during hypoxia on the distribution of blood flow., Methods: The fluorescent microsphere technique was used to compare regional blood flow in 1-month-old rabbits during systemic hypoxia (10% inspired O2) with (n = 9) and without (n = 10) body warming. Blood flow was measured in brain, stomach, small intestine, hindlimb muscle, skin, and kidneys. Arterial blood pressure, whole-body O2 consumption, arterial blood O2 saturation and blood gases were also measured., Measurements and Main Results: In hypoxia all animals decreased body temperature (-2 degrees C). With hypoxia blood flow increased to brain and hindlimb muscle; decreased to stomach, small intestine, and kidneys, and was unchanged in skin. The increase in brain-blood flow maintained O2 delivery at normoxic levels. Rewarming to the normoxic body temperature significantly changed blood flow in hypoxia. Brain blood flow increased by 102 +/- 30% (mean +/- SEM) thereby increasing O2 delivery by 50 +/- 23% above normoxic values. Blood flow also increased to skin, stomach, and small intestine. However, O2 delivery to these tissues remained below normoxic levels., Conclusions: Warming during hypoxia may impose an additional cardiovascular demand. The changes in the pattern of blood flow distribution with mild warming during hypoxia support the hypothesis that warming represents a significant heat stress., (Copyright 2006 S. Karger AG, Basel.)

Background: Palivizumab has been shown to reduce the risk of hospitalization caused by respiratory syncytial virus in children with congenital heart disease (CHD). Guidelines published in 2003 by the Canadian Paediatric Society (CPS) stated that children younger than 24 months with hemodynamically significant CHD should be considered for up to five monthly doses of palivizumab during the winter season., Objective: To assess the impact of CPS guidelines on the use of palivizumab in children with CHD., Methods: Clinical information was reviewed on all patients with CHD who were prescribed palivizumab in 2002-2003 and 2003-2004 and who were followed by one of four paediatric cardiovascular programs in the province of Quebec., Results: Palivizumab was prescribed to 45 children in 2002-2003 and to 146 children in 2003-2004. The number of children receiving more than five doses increased from 10 of 45 (22%) in 2002-2003 to 57 of 128 (45%) in 2003-2004 (P=0.008). One hundred seventeen of 146 children (80%) receiving palivizumab in 2003-2004 met the CPS guidelines versus 38 of 45 children (84%) in 2002-2003 (ie, before the guidelines were published) (P=0.66). Patients not meeting CPS criteria were older than 24 months at the time of the first dose, had hemodynamically insignificant CHD or had lesions adequately corrected by surgery., Conclusions: The number of children with CHD receiving palivizumab prophylaxis increased significantly following the publication of CPS guidelines. The majority of children were eligible for palivizumab according to the current CPS criteria. More patients received more than five doses in 2003-2004 than in 2002-2003.

Objective: To determine whether transient hypoxia in neonatal rats has long-lasting effects on inotropic stimulation of the adult heart., Methods: The hearts of adult male Sprague-Dawley rats (89+/-1 (S.E.M.) days, 432+/-5 g) were studied. Half the animals had been subjected to neonatal hypoxia (FiO(2)=0.12, days 1-10) while the others had not. The peak response of left ventricular pressure (LVP) and the maximum rate of pressure increase (+dP/dtmax) were measured in isolated and perfused hearts during application of dobutamine, isoproterenol, milrinone and betaxolol. Left ventricular myocyte membranes were analyzed for beta receptor density, adenylyl cyclase activity and content., Results: LVP and +dP/dtmax responses to stimulation with dobutamine and isoproterenol were significantly impaired in adult hearts of neonatally hypoxic rats. The inotropic effect of dobutamine was abolished by blockade with the beta(1)-selective antagonist betaxolol. The inotropic effects of the phosphodiesterase inhibitor milrinone were also significantly decreased in neonatally hypoxic adult hearts. There was no difference in left ventricular myocyte membrane beta receptor density of adult hearts whether they were hypoxic neonatally or not. However, left ventricular adenylyl cyclase activity on isoproterenol or forskolin stimulation and adenylyl cyclase levels (type V/VI) were significantly reduced in neonatally hypoxic adult hearts., Conclusions: Neonatal hypoxia in the rat has long-lasting effects on the left ventricular response to inotropic stimulation at maturity likely at least in part due to diminished left ventricular adenylyl cyclase levels.

Objective: To determine the effects of chronic hypoxemia neonatally on the cardiovascular response to acute hypoxemia in adulthood., Methods: Experiments were conducted on adult rats (82+/-2 days) which had been made chronically hypoxemic (hypobaric hypoxia equivalent to FiO(2)=0.14) during the first ten days of life but raised in room air (Neonatally Hypoxemia) as well as on adult rats never previously hypoxemic (Control). The animals were instrumented with catheters in the right common carotid artery and superior vena cava for measurements of mean systemic arterial pressure (MAP), central venous pressure, heart rate (HR), arterial blood gases, and arterial as well as mixed venous O(2) saturation. Oxygen consumption (VO(2)) was measured allowing calculation of cardiac index (CI), stroke volume index (SVI) and systemic vascular resistance index (SVRI). The rats were made acutely hypoxemic by exposure to FiO(2)=0.10 for 20 min., Results: HR increased and MAP decreased to similar extents in both groups during acute hypoxemia. However, SVI and CI increased significantly (P<0.05) during acute hypoxemia in the Neonatally Hypoxemic group (24+/-6%, 41+/-8%) but respectively decreased and did not change in the Control animals (-13+/-6%, 2+/-6%). SVRI fell significantly more during hypoxemia in the Neonatally Hypoxemic animals than in the Control group (36+/-4% vs. 14+/-5%)., Conclusions: Hypoxemia experienced in early life has long-term effects on the cardiovascular response to acute hypoxemia at maturity. This may have important implications for individuals hypoxemic in early life due to congenital cyanotic heart defects or pulmonary disease secondary to prematurity.

Objective: To document the natural history and surgical outcomes for discrete subaortic stenosis in children., Design: Retrospective review., Setting: Tertiary care paediatric cardiology centres., Patients: 92 children diagnosed between 1985 and 1998., Main Outcome Measures: Echocardiographic left ventricular outflow gradient (echograd), and aortic insufficiency (AI)., Results: The mean (SEM) age at diagnosis was 5.3 (0.4) years; the mean echograd was 30 (2) mm Hg, with AI in 22% (19/87) of patients. The echograd and incidence of AI increased to 35 (3) mm Hg and 53% (36/68) (p < 0.05) 3.6 (0.3) years later. The echograd at diagnosis predicted echograd progression and appearance of AI. 42 patients underwent surgery 2.2 (0.4) years after diagnosis. Preoperatively echograd and AI incidence increased to 58 (6) mm Hg and 76% (19/25) (p < 0.05). The echograd was 26 (4) mm Hg 3.7 (0.4) years postoperatively, with AI in 82% (31/38) of patients. Surgical morbidities included complete heart block, need for prosthetic valves, and iatrogenic ventricular septal defects. Eight patients underwent reoperation for recurrent subaortic stenosis. The age at diagnosis of 44 patients followed medically and 42 patients operated on did not differ (5.5 (0.6) v 5. 0 (0.6) years, p < 0.05). However, the echograd at diagnosis in the former was less (21 (2) v 40 (5) mm Hg, p < 0.05) and did not increase (23 (2) mm Hg) despite longer follow up (4.1 (0.4) v 2.2 (0. 4) years, p < 0.05). The incidence of AI at diagnosis and at last medical follow up was also less (14% (6/44) v 34% (13/38); 40% (17/43) v 76% (19/25), p < 0.05)., Conclusions: Many children with mild subaortic stenosis exhibit little progression of obstruction or AI and need not undergo immediate surgery. Others with more severe subaortic stenosis may progress precipitously and will benefit from early resection despite risks of surgical morbidity and recurrence.

We questioned whether the decrease in O2 consumption (VO2) during hypoxia in newborns is a regulated response or reflects a limitation in O2 availability. Experiments were conducted on previously instrumented conscious newborn dogs. VO2 was measured at a warm ambient temperature (30 degrees C, n = 7) or in the cold (20 degrees C, n = 6), while the animals breathed air or were sequentially exposed to 15 min of fractional inspired O2 (FIO2): 21, 18, 15, 12, 10, 8, and 6%. In normoxia, VO2 averaged 15 +/- 1 (SE) and 25 +/- 1 ml . kg-1 . min-1 in warm and cold conditions, respectively. In the warm condition, hypometabolism (i.e., hypoxic VO2 < normoxic VO2) occurred at FIO2

Acute hypoxia in newborns of various species including humans is associated with decreased thermogenesis and a fall in body temperature. We have investigated the cardiorespiratory consequences of correcting the fall in colonic temperature (Tc) during acute hypoxia in newborn cats. Experiments were conducted on 21 unanesthetized kittens (12 +/- 1 d SEM, 244 +/- 8 g) instrumented with catheters in the left common carotid artery and superior vena cava for measurements of systemic arterial pressure, central venous pressure, heart rate, arterial blood gases, arterial O2 saturation (SaO2) and mixed venous O2 saturation. Oxygen consumption (VO2) and CO2 production (VCO2) were also measured. Alveolar ventilation (VA), cardiac index (CI), and systemic vascular resistance index (SVRI) were calculated. These determinations were made in 21% O2 at an ambient temperature (Tamb) of 25 degrees C, and after 80 min of exposure to Fio2 = 0.10. In one group Tamb was maintained at 25 degrees C (n = 8) during hypoxia and Tc fell by 2.7 +/- 0.4 degrees C whereas in a second group Tamb was increased to 35 degrees C for the second 40 min of hypoxia to raise Tc the prehypoxic level (n = 13). VO2, VCO2, VA, SaO2, and systemic arterial pressure during hypoxia did not differ between the animals which were warmed and those which were not. However, CI and heart rate were greater (452 +/- 23 versus 346 +/- 30 mL.min-1.kg-1 p < 0.05, 279 +/- 8 versus 228 +/- 12 beats.min-1 p < 0.05) and SVRI lower (0.115 +/- 0.022 versus 0.153 +/- 0.014 mm Hg.mL-1.min.kg, p < 0.05) during hypoxia in the warmed animals compared with the unwarmed group. Thus, artificially raising Tc during hypoxia resulted in peripheral vasodilation, whereas systemic arterial pressure was maintained by the increase in cardiac output. We conclude that, in the hypoxic kitten, raising Tc to normoxic values elicits a response that may reflect a condition of relative hyperthermia.

The effects of systemic hypoxia on the neurogenic component of hindlimb vascular resistance were studied in six sinoaortic-denervated, anesthetized cats with intact central nervous system. Hindlimb perfusion pressure (PP) was measured under conditions of constant flow of normoxic blood from a donor cat. The neural component of the PP was estimated from the change in PP upon administration of hexamethonium (10 mg/kg i.v.). Ventilation of the recipient cat with 12.5% and 10% O2 was associated with an average 35 +/- 15% (SEM) and 13 +/- 10% decrease, respectively, of the estimated neural component of the PP. In contrast ventilation with 7.5% and 5% O2 produced increases of 27 +/- 7% and 58 +/- 10%, respectively, of the estimated neural component of the PP. Both the vasodilator and vasoconstrictor responses were abolished by hexamethonium (10 mg/kg i.v.). The vasodilator response appeared to be due to withdrawal of alpha-adrenergic tone since it was eliminated by constant infusion of phentolamine to the hindlimb (45 micrograms/ml blood/min). We conclude that, in addition to the already known sympatho-excitation seen in the sinoaortic-denervated cat during severe systemic hypoxia, there is also a sympatho-depressant effect which dominates at more moderate levels of systemic hypoxia.

The relation between arterial O2 tension (PaO2) and the firing rate of sympathetic preganglionic neurons (SPN) was studied in 16 strands of the cervical sympathetic trunk (CST) during graded isocapnic hypoxia in 11 sinoaortic-denervated central nervous system (CNS)-intact, anesthetized cats. SPN firing rate was independent of PaO2 from normoxia down to a PaO2 of 40 Torr. Below this PaO2 level three response patterns were observed, i.e., an excitatory response (n = 8), a depressant response (n = 3), and a mixed response consisting of a depression of firing at less severe hypoxic levels and an increase in firing rate at more extreme hypoxic levels (n = 5). Similar response patterns were also observed in four strands of the CST in three unanesthetized, sinoaortic-denervated, midcollicular decerebrate preparations. Systemic arterial pressure decreased in all cats as PaO2 decreased. Phrenic nerve activity also decreased in all cats with a course resembling that of the depression of sympathetic firing and disappeared at a PaO2 of 20 Torr. The data suggest that systemic hypoxia in the sinoaortic-denervated, CNS-intact or decerebrate animal activates both excitatory and depressant mechanisms acting on SPNs.

The effects on the pressor response to cerebral ischemia (CIR) of superfusion of the ventral medullary surface with artificial cerebrospinal fluid (CSF) containing local anesthetic was investigated in 10 sinoaortic-denervated, anesthetized cats. Prior to application of the local anesthetic, occlusion of the common carotid and vertebral arteries caused an increase in mean systemic arterial pressure (SAP) of 58 +/- 7 mmHg (+/- SE) from an initial level of 98 +/- 6 mmHg. Following 108 +/- 15 s of superfusion with artificial CSF containing 2% procaine, the CIR decreased to 19 +/- 3 mmHg. At this time phrenic nerve activity had been eliminated but basal SAP had only decreased by 14 +/- 2 mmHg, and significant neurogenic vasomotor tone remained. The residual CIR can be accounted for by the passive increase in systemic resistance due to occlusion of the cerebral vascular bed. The effects of procaine were reversible. On attenuation of the CIR, electrical stimulation of pressor points 2-4 mm from the ventral medullary surface was still effective. Autoradiographic analysis following application of 14C-labeled lidocaine showed that attenuation of the CIR occurred when estimated concentrations of the anesthetic sufficient to block nerve conduction extended 85 micron from the ventral medullary surface. These results indicate that the CIR is mediated by superficial structures in the ventral medulla that are not involved in the generation of a major fraction of basal vasomotor tone.

The relation between end-tidal (ET) pCO2 and firing rate of sympathetic preganglionic neurons (SPN) of the cervical sympathetic trunk was studied during hyperoxic hypercapnia in acute C1 or C4 spinal cats. The cats were under barbiturate anesthesia or anemically decerebrate. The firing rate of the majority of the tonically active strands (18/22) increased in hypercapnia and showed a continuous relation to ET pCO2 within the range studied. The firing rate of the remaining 4 strands was unaffected. The maximum increase in firing rate of the responsive strands was 3.7 times the control value on average (range 2.5-14.0). Recruitment of units which were silent in control conditions also occurred. These data demonstrate the existence of a spinal mechanism responsible for excitation of SPN during systemic hypercapnia.

Changes in 2-deoxyglucose (2-DG) uptake in the central nervous system during systemic hypercapnia were determined by the [3H]2-DG autoradiographic method in peripherally chemodenervated rats. Autoradiographs were made from serial transverse sections of the brain and analyzed by a computer-based interactive image processing system for areas having increases or decreases in metabolic activity compared with control animals. The most pronounced change shown by autoradiographs of the hypercapnic animals was a generalized decrease in the metabolism of the gray matter throughout the central nervous system with respect to the normocapnic controls. However, several central structures showed evidence of either no change or an increased metabolism in the hypercapnic animals. In the brain stem these areas were localized to the ventrolateral region of the nucleus of the solitary tract rostral to the obex, around the region of the nucleus retroambiguus, in a region of the ventrolateral medullary reticular formation extending rostrally from the obex to the level of the intramedullary rootlets of the facial nerve, in the region of the ventral nucleus raphe pallidus, and in the region of the lateral parabrachial nucleus. In the diencephalon these regions included the supraoptic nucleus and the dorsal hypothalamic area, extending into the caudal portion of the paraventricular nucleus. The thoracolumbar cord showed activation of the lateral aspects of the dorsal horns, the region of lamina X and the region of the intermediolateral nucleus. These data may be interpreted as a functional map of the central structures activated in hypercapnia in the peripheral chemodenervated rat. It appears likely that these structures are involved in mediating the cardiorespiratory responses associated with the activation of central chemoreceptors by the increased carbon dioxide concentrations.

The effects of systemic hypoxia and hypercapnia on the neurogenic component of hindlimb vascular resistance were studied in 10 unanesthetized acute Cl spinal cats. Hindlimb perfusion pressure (PP) was measured under conditions of constant flow of normoxic and normocapnic blood from a donor cat. Ventilation with 5% CO2 and 10% CO2 in O2 caused increases in PP of 15 +/- 2 (mean +/- SE) mm Hg and 27 +/- 3 mm Hg from a control level of 106 +/- 6 mm Hg during ventilation with 100% O2. Changing the inspired gas mixture from 95% O2 plus 5% CO2 to 12.5%, 10%, 7.5%, or 5% O2 plus 5% CO2 in N2 caused increases in PP of 1.5 +/- 1, 14 +/- 2, 38 +/- 6, and 69 +/- 15 mm Hg respectively from a control level of 121 +/- 9 mm Hg. These vasoconstrictor effects were abolished by ganglionic blockade with hexamethonium (10 mg/kg iv). We conclude that in the acute Cl spinal cat a large part of the population of sympathetic preganglionic neurons in the lumbar spinal cord, controlling vascular smooth muscle of the hindlimb, is excited by systemic hypoxia or hypercapnia over a considerable range of PaO2 and PaCO2 values.

The effect of graded isocapnic hypoxia on the mass activity of the cervical sympathetic trunk and of the phrenic nerve was studied in sinoaortic-denervated, pentobarbital-anaesthetized cats. Under control conditions (normoxia, normocapnia) sympathetic discharge showed (i) a burst of action potentials synchronous with the phrenic nerve burst, which was selectively abolished by procedures suppressing inspiratory neuron activity (inspiration synchronous sympathetic activity, ISSA); and (ii) a lower level of sympathetic activity during expiration (tonic sympathetic activity, TSA). The effects of graded hypoxia on these two components of the sympathetic discharge were different. ISSA showed depression only, which began at inspired PO2 (Pinsp O2) of 58 +/- 10 (mean +/- SEM) mmHg (1 mmHg = 133.3 Pa), became progressively more marked as Pinsp O2 decreased further, and was paralleled by depression of phrenic nerve activity. Both ISSA and phrenic nerve activity were suppressed at Pinsp O2 of 46 +/- 9 mmHg. TSA increased progressively with the lowering of Pinsp O2, beginning at a Pinsp O2 significantly lower than that at which ISSA depression began (50 +/- 13 mmHg, p less than 0.01). In the range of Pinsp O2 values intermediate between the thresholds for ISSA depression and for TSA increase, some animals showed a depression of TSA that reversed to an increase as Pinsp O2 decreased further. During brief (duration 1.5 +/- 0.2 min) episodes of cerebral ischemia produced by occlusion of the brachiocephalic and left subclavian artery, the two components of sympathetic discharge showed responses similar to those observed in hypoxia, namely depression of ISSA as well as depression and enhancement of TSA.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between arterial O2 tension (PaO2) and the firing rate of sympathetic preganglionic neurons (SPN) of the cervical sympathetic trunk was studied during graded isocapnic hypoxia and hyperoxia in unanesthetized acute C-1 spinal cats. In the PaO2 range between 40 and 400 Torr there was no relation between the two variables. Below 40 Torr firing rate increased as PaO2 decreased, reaching an average peak value of ten times control at a PaO2 of 20 Torr. Mean arterial blood pressure (MABP) was also independent of PaO2 between 40 and 400 Torr and increased by an average of 25% at PaO2 values below 40 Torr. Intravenous administration of hexamethonium or phentolamine abolished the MABP response but not the SPN response to hypoxia. Pentobarbital (5-60 mg/kg iv) did not modify the SPN response to hypoxia, although normoxic SPN background firing was considerably depressed. The excitatory effect of hypoxia seems independent of excitatory afferent input and appears to be a general property of SPN.

The organization of pathways within the central nervous system which are activated by aortic baroreceptor input was studied in the urethane anesthetized rat using the 2-deoxyglucose method. [3H]2-deoxyglucose was administered i.v. while either the aortic nerve was electrically stimulated or aortic baroreceptors were physiologically activated by pulse increases in arterial pressure in animals with bilateral denervation of the carotid sinus. Autoradiographs of transverse sections of the central nervous system were developed and analyzed for changes in metabolic activity in discrete regions compared to control animals, as indicated by the density of the photographic emulsion. Electrical stimulation of the aortic nerve resulted in all animals in an increase in the uptake of deoxyglucose in a number of sites throughout the central nervous system, primarily ipsilateral to the site of stimulation. In the brainstem, structures previously implicated in cardiovascular reflexes were labeled. These included the nucleus of the solitary tract, the solitary tract, the dorsal motor nucleus of the vagus, and the nucleus ambiguus. In addition, the inferior olivary nucleus, the parabrachial nuclei and the ventrolateral reticular formation showed increased labeling. In the hypothalamus, increased labeling was observed only in the paraventricular and supraoptic nuclei.